Unsymmetrical n, n&#39;-substituted ethylenediamine and piperazine compounds



UNSYMMETRICAL N,N'-SUBSTITUTED ETHYL- ENEDIAMINE AND PIPERAZINECOMPOUNDS Ansel P. Swain, Springfield Township, Montgomery- County, Pa.,assignor to McNeil Laboratories, Incorporated, Philadelphia, Pa., VaniaNo Drawing. Application December 19, 1952, Serial No. 327,045

6Claims. ((31.260-268) The present invention relates to novel chemicalcompounds and to the method of preparing the same; and, moreparticularly, it relates to unsymmetrical N,N'-disubstitutedethylenediamine compounds possessing valuable sympatholytic properties.i

h There are mentioned in the literature and available on t esympatholytic properties, that is, they have theqability to prevent theactions of epinephrine and similar-neurohormones in the human body andare able to diminish or prevent the activity of the sympathetic nervoussystem. These agentspossess certain limitations, however, which severelyrestrict their field of use. Benzodioxanylmethyl piperidine,benzodioxanylmethyl diethylamine, and benzodioxanylmethyl piperazine,for example, can only be administered by injection and have onlytransient efiects against circulating epinephrine. not usefullyeffective in blocking the sympathetic nervous system and are toxic atthe levels that are only partially effective; they are not active onoral administration. Other compounds, while possessing more definitesympatholytic properties, are limited to administration by injectionsince they have an irritating or corrosive effect on the stomach andintestinal wall it taken orally.

An important advantage of the novel compounds of the present inventionis that they do not produce the toxic effects that have been observed,following either parenteral or oral administration of othersympatholytic agents; that is, they do not produce nausea, vomiting,tissue irritation, coronary constriction, and the like effects on theheart, blood vessels and viscera. f

The principal object of the'present invention is to provide new chemicalcompounds possessing advantageous pharmaceutical properties.

Another object of the invention is to provide chemical compoundspossessing valuable sympatholytic properties, which can be administeredorally as well as by injection.

A further object is to provide chemical compounds which are effective inblocking the sympathetic nervous system as well as injected epinephrineand which may be administered orally as well as by injectionfor thesepurposes. I

Other objects, including the provision of a method of making the novelcompounds, will be apparent from a consideration of thisspecificationand the claims.

-In copending applications of Ansel P. Swain Serial Number 327,043 and327,044, both filed December 19, 1952, aredisclosed and claimedcompounds related to those of the present invention as well as themethod of preparing them, and reference may be made, if de sired, tosaid copending applications as'amplifying the present disclosure.

The novel compounds of the present invention are unsymmetricalN,N-disubstituted ethylenediamine compounds having the followingfundamental structural where R and Ri are selected from the groupconsisting a corporation of Pennsyl market certain chemical compoundswhich possess 2,695,295 1 Patented Nov. 23,

1 where R: is selectedfrom a phenyl group p Q and al,4-benaodioxan-2-ylmethyl group n-oni where Ra is selected from aphenyl group and a Z-phenoxyethyl group V where R, R4 and R5 areselected from the group con- Such compounds are plete the piperazinering CHr-CE:

sistingof hydrogen, methyl and methoxy, Ra being a phenyl group onlywhen N: is a 1,4-benzodioxyanylmethyl group.

The products of the present invention thus comprise three closelyrelated groups of compounds, namely, N- l,4-benzodioxan-2-ylmethyl)-N"phenyl ethylenediamine compounds having theformula:

the N-( l,4-benzodioxan-2-ylmethyl) N'-(2-phenoxyethyl) ethvlenediaminecompounds having the following formu a:

and the N-phenyl-N -(Z-phenoxyethyl) ethylenediamine compounds havingthe formula: V

. s N\ N CHrCHrO CHr-Cz From the standpoint of optimum. sympatholyticactivity, the preferred compounds are those in which R and R1 jointhrough a dimethylene linkage to complete the piperazine ring; and,hence, the preferredcompounds are the N,N'-disubstituted piperazinecompounds corresponding to the above formulae. r Referring to R4, R5 andR7 in the above formulae, the exact. position of this group, when methylor methoxy on the benzene ring is not critical and it maybe on anyavailable position, or the product may evenbe made up of a mixturetheposition of the R4, Rsor R groups. v

of compounds differing as to The compounds of the present invention allpossess valuahle sympathol'yti'c properties that are efiective inblocking epinephrine and other rieurohormones Whether the latter beinjected or elaborated physiologically .in the body. Thecompounds-findparticular utility, in addition to known uses forsympatholytic agents, in the treatment of hypertension. Moreover, thecompounds can readily be administered orally without being toxic orproducing other deleterious physiological effects, and are effective forthe stated purposes when so administered. The compounds will range inactivity from that of prior available sympatholytic agents to anactivity many times greater, particularly when compared on oraladministration.

In the compounds of the present invention, there are two basic nitrogensto which one or two equivalents of acid may be addedto form amonoor disalt. Hence, the compounds of the invention'may be prepared and/ oremployed either as the base" or as a salt. Thus, for example, thestructural formula for the dihydrochlorides of the compounds of thepresent invention may be written as follows:

In view of the fact that the salts differ from the bases only in theaddition of the acid to one or both of the nitrogen atoms referred to,and are characterized by the same fundamental 'structu'ral'formula, thesalts as well as the bases are included within thescope of thisapplication and of the' claims'whe'rever reference is made to a compoundcomprising a defined fundamental structural formula.

The acid forming the salt may be any inorganic or organic aciddesired,'for'example, hydrochloric, hydrobromic, hydroiodic,nitric,'sulphuric phosphoric, and the like; acetic, proprionic, caproic,stearic, and other acids of this series,and the like; crotonic, oleic,oxalic, citric, tartaricylactic, benzoic, naphthoic, picric, salicyclic,dilituric, methane'sulphonic, camphor sulphonic, and the like. If a saltisto be administered any toxicity which may be imparted by the acidshould be taken into consideration as wellknown in the art.

The compounds ofthe present'invention may be readily prepared byreacting one mole of an ethylenediam'ine base, or a salt or hydratethereof, with one mole ofa compound providing the desired R2 group,following which one mole of the' resulting N-substituted ethylenediamine product-may be reacted with a mole of compound providing thedesired R3 group. Of course, if the N-substitutedethylenediamine-possessing the desired R2 or R3 group is available, itmay merely be reacted with one mole of a compound'providing theremaining R2 or R3 group to provide the desired product, and this is thepreferred method in the case of the phenylpiperazine compounds. Where,in the final product, R2 is to be a benzodioxyanylmethyl group and R3 isto be a phenyoxyethyl group, the product maybe prepared by reacting onemole of an ethylenediamine (base, hydrate or salt) with'one mole of thedesired benzodioxyanylmethyl halide, sulfate, or phosphate, and thenwith one mole of the desired 2- phenoxyethyl halide, sulfate, orphosphate. The order of the reactions is immaterial. When either R2 orR3 is to be a phenyl group, and R and R1 are to form a joineddimethylene linkage completing the piperazine ring, it'is preferredfirst to prepare the phenyl piperazine, as by reacting a salt, forexample, the hydrochloride of aniline or appropriate me'thylormethoxy-substituted aniline with a salt, such as the hydrochloride, ofdiethanolamine. References have been made above to halide derivatives ofthe various reactants, and these may be suitable chlorine, bromine,iodine, and the like, derivatives.

In preparing the N substituted ethylenediamine, that is, in carrying outthe first reaction step discussed above, it maybe desirable, in'ordertopreventreactionoccurring at both nitrogen atoms, initiallyto provide areadily removable blocking group atone of the nitrogen atomson thediamine. Examples of such blocking groups are the carboalk'oxy groups,-such as the carbethoxy group (C2H5O0C-) and the jfcarbobe'nzyloxy"group.The presence of such" a' 'grbupinsures the formationof the desiredN-substituted ethylenediamineproduct of the first reaction step.Following this reaction step,- the'bloc'kin'g' 4 group may be removed,as by hydrolysis, and the second reaction step carried out to providethe final N,N'-disubstiuted ethylenediamine compound.

The reaction between the ethylenediamine compound and the compoundsproviding the desired R2 and Rs groups may be carried out in alkalineaqueousor alcoholic' medium. When an aqueous medium is employed, thealkali used is advantageous sodium hydroxide; and when an alcoholicmedium is employed,'the alkali used isa'dvantageou'sly sodiumcarbonate.- It is desi'rableto heat the" reaction mixture until thereaction is complete, and in this connectionrefluxin'g is preferred.After the reaction is as complete as desired, the product may beconveniently separated from the reaction mixture by removal of part orall of the solvent used, or by filtration if the product is a solid. Ifthe product is liquid, it may be removed by extraction with a suitablesolvent such as ether. In isolating the product, itmay be desirable-torecover if as a salt'and this maybe accomplished by treating thereaction product or an fextract'thereof' with a suitable acid of thetype discussed hereinabove.

Thefollowing examples serve to illustrate further the present invention.

Example I ethanolamine"hydrochloridesat 180-190" Cafor 6-8 hours; makingthe reaction mixture alkaline, extracting with ether and fractionallydistilling the residue after removal of the solvent ether), 36.5 g. (0.2gram mole) of 2-chloromethyl-l,4 benzodioxan, and 7.2 g. (0.18gta'mmole) of sodium hydroxide in 7.2 'mlaof water is'h'e'ated at 100l10 C.for 62, hours; The solidwhich .s'eparates on cooling is washed withwater and crystallized from a mixture of acetone and water togivelust'rous crystals melting at 815-82 C. The calculated N content ofC19H22N2Oz' is 9.0; thatffound is 8.8. The compound is'N-(1,4-benzodioxan-2-ylmethyl)-N'-phenylpiperazine having the formula:

By substituting N-phenyl-ethylenediaminefor the N- phenylpiperazinein-the above procedure, N-(l,4'-benzodioxan-2-ylmethyl) -N' phenyIethIenediamine may be prepared.

Likewise by substituting N-(ortho-, meta-, or paramethylphenyl)piperazin'e 'orethylenediamine and N- (ortho- -meta-, orpara-metho'xyphenyl) piperazine' or solution causes a white solid toseparate.

ethylenediamine, respectively,'for the'N-phenylpiperazine, thecorresponding N-m'ethylphenyland N met hoxyphenylplperazine orethylenediamine products may be prepared; while the correspondingN-methyl-1,4-benzodioxan-2-ylm'ethyl) "or N (methoxy-1,4-benzodioxan-2-ylmethyl) products may be prepared by substitutingthe 5-, 6-, 7- or8-methylor'methoxy derivatives of 2-chloromethyll',4-benzodioxan for the2-'chlorome'thyl-l,4- benzodioxanof this example.

I Example 11 g mixture of 2.7 g. (0.01 gram mole) ofN-(lA-benzodroxan-Z-ylmethyl) piperazine hydrochloride, 2.0 g. (0.01gram mole) of 2-phenoxyethyl'bromide, 2.1 g. (0.02 gram mole) ofanhydroussodiurn carbonate,- and 250 ml. of methanol is refluxed for 58hoi1rs. J The inorganic salts are'removedby'filtration and washed'withBy substituating 2-(ortho-, meta-, or para-methylphenoxy) ethyl bromideor 2-(ortho-, meta-, or paramethoxyphenoxy) ethyl bromide for the2-phenoxyethyl bromide in the above reaction, the corresponding N-( 1,4-benzodioxan-Z-ylmethyl)-N'-[2-methylphenoxy) ethyl] piperazine andN-(1,4-benzodioxan-2-ylmethyl)-N'-[2- methoxyphenoxy) ethyl] piperazinecompounds, respectively, may be prepared.

By substituting 5-, 6-, 7- or S-methylor methoxy derivatives ofN-(l,4-benzodioxan-2-ylmethyl) piperazine hydrochloride for theN-(1,4-benZodioxan-2-ylmethyl) piperazine hydrochloride of this example,the corresponding products may be prepared. Likewise, as in Example I,the corresponding 1,4-benzodioxan-2-ylmethyl ethylenediaminehydrochlorides may be used to provide the correspondingN-(1,4-benzodioxan-2-ylmethyl)-N'- (Z-phenoxyethyl) ethylenediamineproducts.

Example III A mixture of 5.1 g. (0.0315 gram mole) ofN-phenylpiperazine, 6.3 g. (0.0315 gram mole) of 2-phenoxyethyl bromideand 1.3 g. (0.0315 gram mole) of sodium hydroxide in 4 ml. of water isrefluxed for 3.5 hours. The solid which forms on cooling is pulverizedin water and collected by filtration. After two crystallizations from amixture of acetone and water, white platelets of the monohydrate areobtained which melt at 80-81 C. The calculated N content for is 9.3;that found is 9.2.

When melted under vacuum, the above compound loses its molecule of waterto give the anhydrous compound melting at 80-81 C. The calculated Ncontent for CmHzzNzO is 9.9; that found is 9.9.

The compound is N-phenyl-N'-(2-phenoxyethyl) piperazine having theformula:

CHa-C H2 N-CHz-O Hz-O- CHE-CH2 By substituting 2-(ortho-, meta-, orpara-methylphenoxy) ethyl bromide or 2(ortho-, meta-, orparamethoxyphenoxy) ethyl bromide for the 2-phenoxyethyl bromide in theabove reaction, the corresponding N- phenyl-N-[2-methylphenoxy) ethyl]piperazine and N- phenyl-N'-[Z-methoxyphenoxy) ethyl] piperazinecompounds, respectively, may be prepared.

Likewise, by substituting N-methylphenylpiperazine orN-methoxyphenylpiperazine for the N-phenylpiperazine, the correspondingN-methylphenyland N-methoxyphenyl-N-(Z-phenoxyethyl) piperazineproducts, respectively, may be prepared. And, as in Example I, thecorresponding N-phenylethylenediamines may be substituted for theN-phenylpiperazine to prepare the correspondingN-phenyl-N'-(2-phenoxyethyl) ethylenediamine products.

Considerable modification is possible in the selection of varioussubstituents and combinations thereof, as well where R and R1 areselected from the group consisting of hydrogen and a joined dimethylenelinkage -CH2CH2 to complete the piperazine ring OHPCH:

CHrCz where R2 is selected from a' phenyl group and a1,4-benzodioxan-2-ylmethyl group CH2 (HI-CH? 0 and where R3 is selectedfrom a phenyl group and a Z-phenoxyethyl group R3 being a phenyl grouponly when R2 is a 1,4-benzodioxan-Z-ylmethyl group, R4, R5 and R in theabove formulae being selected from the group consisting of hydrogen,methyl and methoxy.

2. N (1,4 benzodioxan -'2 ylmethyl) N piperazine.

- phenyl- 3. N (1,4 benzodioxan 2 ylmethyl) N (2- phenoxyethyl)piperazine.

4. N phenyl N (2 phenoxyethyl) piperazine.

5. N 1,4 benzodioxan 2 ylmethyl) N (2- phenoxyethyl) ethylenediamine.

6. N (1,4 benzodioxan 2 ethylene-diamine.

ylmethyl) N phenyl- No references cited.

1. UNSYMMETRICAL N,N''-DISUBSTITUTED ETHYLENEDIAMINE COMPOUNDS HAVINGTHE FOLLOWING FUNDAMENTAL STRUCTURAL FORMULA: